The invention relates to a bone graft substitute and a method for manufacturing a bone graft substitute.
The following definitions shall be used throughout the description:    Resorption=degradation=process by which a material is removed from the human body.    Scaffold=matrix=porous material.    Macropores=here, we define macropores as pores that have a diameter superior to 30-50 microns.    Micropores=pores with a diameter in the range of 0.1 to 20-30 microns.    Nanopores=pores with a diameter smaller than 100 nm.    Tortuous=tortuous pores are pores that do not have a straight shape (e.g. cylindrical, sphere), but a complex shape, such as a helix, with a large aspect ratio (ratio between the longest and the shortest pore dimension).    Tortuosity=Tortuosity is defined as the ratio between the distance required to join two points in a porous structure through the porous network and the direct distance (with a straight line). Tortuosity values are by definition larger than 1 and often larger than 3.
Calcium phosphate bone graft substitutes have proved to be very good bone graft substitutes: the materials have an excellent biocompatibility and depending on their exact composition, might also be degraded over time and replaced by new bone. One particularly successful material is β-tricalcium phosphate [β-Ca3(PO4)2] or shortly [β-TCP].
In past years, many studies have showed the importance of calcium and phosphate ions on the cellular response of bone cells, such as osteoblasts (“bone-forming cells”) and osteoclasts (“bone-resorbing cells”). For example, it is known that a small increase of calcium concentration down-regulates osteoclast activity and up-regulates osteoblast activity. Also, it has been shown that increased calcium ion concentrations could trigger osteoblasts to produce bone morphogenetic proteins such as BMP-2 and BMP-4. We have therefore surprisingly found that calcium phosphate bone graft substitutes can be used as drug delivery systems (Ca and phosphate ions being the drugs). The control of calcium and/or phosphate ions release enables also a control of the in vivo properties of calcium phosphate materials.
Generally, it is desirable to have a cell-mediated degradation (e.g. osteoclasts) rather than having a purely physico-chemical degradation, i.e. dissolution, because a cell-mediated degradation ensures that material degradation is not too fast compared to bone formation. However, by just relying on cells to reach material degradation and hence calcium and phosphate release, it is not possible to control the up-regulation or down-regulation of cells in the close surroundings of the material.
It is an object of the invention to provide a bone graft substitute in the form of an implantable three-dimensional scaffold comprising calcium phosphate and having pores and which is impregnated with a calcium and/or phosphate containing substance whereby the dissolution rate DRS of said scaffold is slower than the dissolution rate DRD of said calcium and/or phosphate containing substance.
The advantage of the bone graft substitute according to the invention lies in the improved in vivo response of calcium phosphate bone substitutes through selective calcium or phosphate release.
It is a further object of the invention to provide a method for manufacturing a bone graft substitute characterized by impregnating a three-dimensional scaffold comprising calcium phosphate having interconnected pores with a calcium and/or phosphate containing substance; whereby the chemical composition and integrity of said scaffold remains essentially unaffected by said impregnation with said calcium and/or phosphate containing substance. The impregnation can be effected e.g. by spraying, soaking, tipping.
It is a further object of the invention therefore to load a matrix or scaffold that is degraded by cells like β-TCP with a compound that can spontaneously dissolve in vivo, like calcium chloride (CaCl2). The main condition for that purpose is to use a compound that is soluble in vivo. Further in the text, the term of “scaffold” will be used to designate a material resorbed by cell-mediation and the term of “drug” when reference is made to the compound that is soluble in vivo and contains calcium and/or phosphate ions.
Typical calcium phosphate bone graft materials of interest for the scaffold (beside β-TCP) are hydroxyapatite (Ca5(PO4)3OH; HA; sintered or non-sintered), dicalcium phosphate (CaHPO4; DCP), octacalcium phosphate (Ca8H2(PO4)6.5H2O; OCP), α-tricalcium phosphate (α-Ca3(PO4)2; α-TCP), α-calcium pyrophosphate (α-Ca2P2O7; α-CPP), and β-calcium pyrophosphate (β-Ca2P2O7; β-CPP). Of interest are also all calcium phosphates having the general apatite structure according to x-ray diffraction, but not having the exact stoichiometry of hydroxyapatite. This includes for example calcium-deficient hydroxyapatite (Ca9(PO4)5(HPO4)(OH); CDHA—sometime called “tricalcium phosphate”), carbonated apatites, and more generally all ion-substituted apatites.
All potential scaffolds can also contain some foreign ions in their structure (not only hydroxyapatite). Surprisingly it has been found that many ionic substitutions exist in calcium phosphates. Of particular interest are Mg, Sr, Zn, Si, Na, K, Li and Cl as potential ions for b-TCP, b-CPP, a-CPP and a-TCP. For HA, OCP, DCP and DCPD, the latter ions as well as CO3−2 ions or SO4−2 ions can be used.
Typical calcium-containing ionic materials that can be used as calcium “drug” are calcium chloride (anhydrous: CaCl2, monohydrate: CaCl2.H2O, dihydrate: CaCl2.2H2O, or hexahydrate: CaCl2.6H2O), dicalcium phosphate dihydrate (CaHPO4.2H2O; DCPD), calcium sulphate dihydrate (CaSO4.2H2O; CSD), calcium sulphate hemihydrate (CaSO4.½H2O; CSH), calcium sulphate (CaSO4), calcium acetate (anhydrous: Ca(C2H3O2)2, monohydrate: Ca(C2H3O2)2.H2O, or dihydrate Ca(C2H3O2)2.2H2O), calcium citrate (Ca3(C6HSO7).4H2O), calcium fumarate (CaC4H2O4.3H2O), calcium glycerophosphate (CaC3H5(OH2)PO4), calcium lactate (Ca(C3HSO3)2.5H2O), calcium malate (dl-malate: CaC4H4O5.3H2O, l-malate: CaC4H4O5.2H2O, or malate dihydrogen: Ca(HC4H4O5)2.6H2O), calcium maleate (CaC4H2O4.H2O), calcium malonate (CaC3H2O4.4H2O), calcium oxalate (CaC2O4), calcium oxalate hydrate (CaC2O4.H2O), calcium salicylate.(Ca(C7H5O3)2.2H2O), calcium succinate (CaC4H6O4.3H2O), calcium tartrate (d-tartrate: CaC4H4O6.4H2O; dl-tartrate: CaC4H4O6.4H2O; mesotartrate: CaC4H4O6.3H2O), and calcium valerate (Ca(C5H9O2)2).
Typical phosphate-containing ionic materials that can be used as phosphate “drug” are DCPD, sodium phosphate (Na2HPO4, NaH2PO4 or a mixture thereof; non-hydrated or hydrated species like Na2HPO4.2H2O, Na2HPO4.7H2O, Na2HPO4.12H2O, NaH2PO4.H2O, NaH2PO4.2H2O), calcium glycerophosphate (CaC3H5(OH2)PO4), potassium orthophosphate (K3PO4), dihydrogen potassium orthophosphate (KH2PO4), monohydrogen potassium orthophosphate (K2HPO4), and sodium orthophosphate (Na3PO4.10H2O and Na3PO4.12H2O).